Leukotrienes are a family of endogenous metabolites of arachidonic acid and play an integral role in regulating inflammatory events. Since their discovery in the late seventies, many have worked to determine the biosynthesis of leukotrienes with an eye toward mediating the inflammatory responses. The focus of much of this work concerned the enzymes used in leukotriene biosynthesis, particularly the first enzyme in the cascade, 5-lipoxygenase. This work has produced a number of drug candidates including the anti-asthmatic, zileuton, which is currently in clinical trials.
In the nineties, work surrounding the search for 5-lipoxygenase inhibitors expanded with the discovery of the 5-lipoxygenase activating protein, FLAP. FLAP is a membrane protein which enhances the catalytic activity of 5-lipoxygenase. Although the precise mechanism of this cooperation is unknown, it has been shown that compounds which bind to FLAP, inhibit the action of 5 lipoxygenase in whole cell assays but are inactive in broken cell enzyme assays. This work has lead to a number of interesting compounds, including MK-0591, an anti-asthmatic agent. ##STR2##
The compounds of the invention are potent 5-lipoxygenase inhibitors many of which are significantly more potent in whole cell assays, than in broken cell enzyme assays. Like other 5-lipoxygenase inhibitors these compounds are useful in the treatment of disease states associated with inhibition of leukotriene biosynthesis such as rheumatoid arthritis, asthma, hypersensitivity, myocardial ischemia, psoriasis and inflammatory bowel syndrome.